tbuckley/cabot-search huggingface dataset:
Abstract 5347: Selective targeting deacetylase 3 (HDAC3) and HDAC8 by PROTACs
Authors: Yufeng Xiao, Seth Hale, Nikee Awasthee, Xuan Zhang, Yi Liu, Zhiguang Huo, Dongwen Lyu, Lei Wang, Weizhou Zhang, Megan Mosteiro, Daiqing Liao, Guangrong Zheng
Journal: Cancer Research (2023)

Abstract Histone deacetylases (HDACs) are enzymes that play an essential role in multiple cellular processes such as DNA transcription, translation, replication, recombination, repair, and metabolism, and their dysregulation can be linked to many different diseases. Most commonly, the overexpression of HDACs is found in various cancer types including hematologic cancers, as well as solid malignancies. Of the many HDACs found in the body, class I HDACs, which consist of HDACs 1, 2, 3, and 8, play an essential role in activating oncogenes underlying tumorigenesis, disease progression, and treatment resistance. Several HDAC inhibitors (HDACis) have been approved for cancer treatment, however, they are pan-inhibitors. This lack of specificity poses many disadvantages for HDACis, including toxicity and other off-target effects. Isozyme-selective inhibitors may reduce these off-target effects and thus enhance their safety. Though favorable, selectivity is difficult to achieve from conventional inhibitors due to the highly homologous catalytic domain among HDAC isozymes. In addition, several HDAC isozymes have deacetylase-independent scaffolding functions that cannot be blocked by traditional inhibitors. Recently, there have been advances in Proteolysis Targeting Chimera (PROTAC), an emerging drug discovery technology designed to hijack cell’s existing protein degradation machinery, the ubiquitin-proteasome system (UPS) to selectively degrade target proteins. Selective degradation by PROTAC is a potential solution to many of the concerns associated with current HDACis. Previously, we reported an HDAC3-selective PROTAC, XZ9002, and following that we reported the discovery of PROTAC YX968, which can degrade both HDAC3 and HDAC8 isozymes with single-digit nanomolar DC50, this highly potent dual degrader exhibits distinct effects on modulating gene expression and is much more potent in inhibiting cancer cell proliferation compared to XZ9002. Based on this, we are further modifying the PROTACs to be selective for HDAC8. The HDAC3, HDAC8 selective degrader and HDAC3 and HDAC8 dual degrader we developed could be useful chemical probes to dissect the complex biological function of HDAC3 and HDAC8 and potential therapeutics for treating cancer. Citation Format: Yufeng Xiao, Seth Hale, Nikee Awasthee, Xuan Zhang, Yi Liu, Zhiguang Huo, Dongwen Lyu, Lei Wang, Weizhou Zhang, Megan Mosteiro, Daiqing Liao, Guangrong Zheng. Selective targeting deacetylase 3 (HDAC3) and HDAC8 by PROTACs. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5347.
Abstract 563: Preclinical development of YL202, a novel HER3-targeting antibody-drug conjugate (ADC) with novel DNA topoisomerase I inhibitor for treatment of solid tumors
Authors: Jian Xu, Qing Zong, Liang Zhu, Qigang Liu, Sasha Stann, Jiaqiang Cai
Journal: Cancer Research (2023)

Abstract HER3, a member of the HER family, is over-expressed in cancer cells and further elevated after HER2/EGFR/endocrine targeting treatment. YL202 is a novel HER3-targeting antibody-drug conjugate (ADC) structurally composed of a human anti-HER3 antibody, protease-cleavable linker, and a novel topoisomerase I inhibitor. This ADC was prepared using MediLink’s TMALIN platform, a proprietary tumor microenvironment activable linker-payload platform, which achieved a high drug-to-antibody ratio through homogeneously conjugated and favorable hydrophilic linker-payload. In preclinical studies, YL202 exhibited strong reactivity, highly internalization and potent cytotoxicity toward tumor cells. YL202 also demonstrated significant dose-dependent antitumor activity in cell line- and patient-derived xenograft (CDX and PDX) mouse models representing several cancer types and could induce complete tumor regressions with no observable toxicity. YL202 showed stable PK profile with overlapping ADC and TAb curves in a 28-day cynomolgus monkey study. GLP toxicity studies using cynomolgus monkeys showed that YL202 is well tolerated with calculated therapeutic index (TI, HNSTD/MED) of ~100 for repeat dosing. No lung or platelet toxicity findings were observed at doses up to the maximum tolerated dose (MTD). Based on these preclinical results, it demonstrates that YL202’s advanced ADC design results in an increased therapeutic margin, and YL201 could be further developed in HER3 positive cancer patients. Citation Format: Jian Xu, Qing Zong, Liang Zhu, Qigang Liu, Sasha Stann, Jiaqiang Cai. Preclinical development of YL202, a novel HER3-targeting antibody-drug conjugate (ADC) with novel DNA topoisomerase I inhibitor for treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 563.
Abstract 5747: A novel combination therapy of arenavirus vectors and PD1-IL2v strongly potentiates tumor specific T cell responses resulting in synergistic anti-tumor efficacy
Authors: Judith Strauss, Diana Reckendorfer, Kimberly Pojar, Laura Codarri Deak, Valeria Nicolini, Roger Sutmuller, Christian Klein, Pablo Umaña, Klaus K. Orlinger, Henning Lauterbach
Journal: Cancer Research (2023)

Abstract It is undisputed that CD8 T cells play a critical role in controlling tumor growth and killing tumor cells, and that tumor specific T cells are essential for clinical responses to immune checkpoint inhibitors. Yet, the induction and maintenance of functional tumor antigen specific T cell responses represent still one of the greatest challenges in cancer immunotherapy. Therapeutic cancer vaccines based on engineered arenavirus vectors have been shown preclinically to overcome self-tolerance to tumor associated antigens (TAA) and mount unprecedented T cell responses, both, in preclinical tumor models as well as HPV16+ cancer patients in an ongoing Phase 1/2 trial. The novel PD-1 targeted IL-2 variant (PD1-IL2v) was created to maximize the potency of IL-2R activation of effector T cells while overcoming the toxicities of wildtype IL-2. Cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell was recently shown to promote differentiation of stem-like CD8 T cells into better effectors and was therefore identified as an ideal compound for combination therapies with arenavirus vectors. Combination of vectors encoding tumor associated foreign or self-antigens with PD1-IL2v lead to a massive, up to 60-fold, increase of peripheral tumor specific CD8 T cell numbers compared to vector treatment alone. Notably, frequency of peripheral regulatory T cells was not enhanced by this combination. The massive increase of TAA specific CD8 T cells was associated with synergistic anti-tumor efficacy in two independent tumor models, resulting in longer survival times and up to 60% complete responders. Complete tumor clearance resulted in a stable memory T cell population and protection against tumor re-challenge. Ongoing studies will address modifications of the tumor microenvironment and further characterization of tumor infiltrating T cells upon combination therapy. These preclinical data establish the combination of arenavirus vectors and PD1-IL2v as a promising next generation cancer immunotherapy. Citation Format: Judith Strauss, Diana Reckendorfer, Kimberly Pojar, Laura Codarri Deak, Valeria Nicolini, Roger Sutmuller, Christian Klein, Pablo Umaña, Klaus K. Orlinger, Henning Lauterbach. A novel combination therapy of arenavirus vectors and PD1-IL2v strongly potentiates tumor specific T cell responses resulting in synergistic anti-tumor efficacy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5747.
Abstract 5196: Novel humanized CD36 mouse model for therapeutic studies
Authors: Linlin Wang, Chang Liu, Rebecca Soto, Chengzhang Shang, Qingcong Lin
Journal: Cancer Research (2023)

Abstract Activation of oncogenic signaling pathways can be mediated by various transporters on tumor cells that facilitate trafficking of lipids. CD36 has been identified as a fatty acid transporter and participates in tumor growth and drug resistance. To explore potential therapeutic strategies targeting CD36, we generated a human CD36 knockout/knock-in in situ (B-hCD36) mouse model to evaluate the efficacy of anti-human CD36 antibodies. We first confirmed human CD36 gene and protein expression in B-hCD36 mice by RT-PCR and flow cytometry, respectively. We next observed that the overall development, differentiation, and distribution of splenic, blood and lymph node immune cells were similar between wild-type C57BL/6 and B-hCD36 mice. Lastly, in vivo efficacy studies using anti-human CD36 antibodies alone or in combination with anti-mouse PD-1 antibodies, were effective in controlling MC38 tumor growth in B-hCD36 mice. Our data demonstrates that B-hCD36 mice are a powerful preclinical model for in vivo efficacy evaluation of anti-human CD36 antibodies. Citation Format: Linlin Wang, Chang Liu, Rebecca Soto, Chengzhang Shang, Qingcong Lin. Novel humanized CD36 mouse model for therapeutic studies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5196.
Abstract 5199: B7-H3 &amp; PD-L1 double-humanized BALB/c mouse: a novel animal model for preclinical studies of human B7-H3 antibodies or bispecific antibodies
Authors: Shiying Guo, Lingyu Song, Xin Qin, Jianming Xu, Hongyan Sun, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao
Journal: Cancer Research (2023)

Abstract Immune checkpoint molecule B7-H3, also known as CD276, is a member of the B7-CD28 family of immunomodulatory proteins. It is a type I membrane protein with sequence similarities to the extracellular domain of programmed death-ligand 1 (PD-L1). B7-H3 is highly expressed in most human cancers, but has limited distribution in normal tissues, remaining elusive of its receptor. Due to its promising safety as a dominant tumor target, various strategies have been developed to modulate the effect of B7-H3 via monoclonal antibodies, bispecific antibodies, ADC, or CAR-T. To study the effect of these therapies in an immunocompetent mouse model, we established a double humanized B7-H3 and PD-L1 mouse model on BALB/c background (BALB/c-hB7-H3/hPD-L1). In this model, the extracellular domain of murine fragments was replaced by the human counterparts while the trans-membrane and cytoplasmic domain were kept intact. When engrafted with CT26 colon cancer cells, which stably overexpress human B7-H3 and PD-L1 while endogenous murine counterparts were knocked out, the tumor growth was inhibited certain degree by anti-B7-H3 antibody (8H9 Biosimilar, 20mpk, TGI=18.56%) treatment while inhibited significantly after the monotherapy of anti-PD-L1 (Tecentriq, 3 mpk, TGI=55.89%, p&amp;lt;0.001). The same dosage combination of anti-B7-H3 and anti-PD-L1 had a significant inhibition on tumor growth (TGI=76.85%, p&amp;lt;0.001), and had a synergistic effect (CDI&amp;lt;0.7) compared with the monotherapy. Analysis of tumor-infiltrating lymphocytes (TILs) at the end of the efficacy study showed that the proportion of CD45+ immune cells was significantly increased in all of the treated groups. The NK cells were significantly increased and the Treg cells were significantly decreased especially in the combined treatment group. Based on the above, the B7-H3 and PD-L1 double humanized mouse model is suitable for the pre-clinical evaluation of mono or combined immune checkpoint blockade with anti-human B7-H3 and PD-L1 therapy. Citation Format: Shiying Guo, Lingyu Song, Xin Qin, Jianming Xu, Hongyan Sun, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao. B7-H3 &amp; PD-L1 double-humanized BALB/c mouse: a novel animal model for preclinical studies of human B7-H3 antibodies or bispecific antibodies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5199.
Abstract 3824: Remodeling of anaplastic thyroid cancer cell signaling and immune landscape by natural alkaloid berberine
Authors: Tara Jarboe, Kaci Kopec, Nicole R. DeSouza, Jan Geliebter, Raj K. Tiwari, Xiu-Min Li
Journal: Cancer Research (2023)

Abstract Anaplastic thyroid cancer (ATC) is universally diagnosed as Stage IV with a five-year-survival of 4%, illuminating its dreadful prognosis. ATC is undifferentiated, has an inflammatory tumor microenvironment (TME), and metabolic dysregulation. As it is refractory to all established therapies, we propose a novel therapeutic - Berberine (BBR), a natural plant alkaloid, with numerous cellular targets that can potentially reprogram ATC’s aggressive phenotype. This research comprehensively examines the multitarget efficacy of BBR. Following initial dose response studies, all assays used 100µM concentration of BBR or DMSO vehicle control for 24-hour exposure. To model the ATC tumor microenvironment, monocyte cell line U937 cells were activated and polarized into a proinflammatory macrophage phenotype. In the presence of berberine at the activation and polarization stages, 33 soluble inflammatory mediators were downregulated in the conditioned media compared to controls. Targeting the aggressiveness of anaplastic disease, berberine slowed proliferation by 50% selectively in ATC cells from 48 to 72 hours, while sparing the immortalized normal thyroid cells. BBR also delayed wound healing by 30% in ATC cells after 24, 48, and 72 hours. These observations were substantiated by Western blot analysis of ATC and immortalized normal cells where BBR decreased phosphorylation of MEK, ERK, and ribosomal protein S6, crucial downstream regulators of the pro-proliferative and pro-survival pathways and increased phosphorylation of AMPKα, activating its anti-tumor and regulatory effects. Validation of in vitro findings via RNA-Seq was conducted by Genewiz from Azenta Life Sciences and Qiagen’s Ingenuity Pathway Analysis was used for in silico modeling. Greater than 400 significantly differentially expressed genes were identified suggesting that BBR regulates mitochondrial metabolism, cholesterol biosynthesis, glycometabolism, apoptosis, inflammation, and proliferation. BBR’s ability to alleviate inflammatory mediators in the TME, depress overactive cell signaling, and regulate metabolism to make it a more targetable cancer reveals it as an interesting candidate to prime ATC for combination therapy. Citation Format: Tara Jarboe, Kaci Kopec, Nicole R. DeSouza, Jan Geliebter, Raj K. Tiwari, Xiu-Min Li. Remodeling of anaplastic thyroid cancer cell signaling and immune landscape by natural alkaloid berberine. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3824.
Abstract 6053: Sulfation is required for prostate cancer xenograft tumor formation but is dispensable for cell viability<i>in vitro</i>
Authors: Ko-Chien Chen, Yonhong Liu, Chenchu Lin, Er-Yen (Nick) Yen, Francesca Citron, Xingdi Ma, Tan Lin, Philip Lorenzi, Florian Muller, Ronald DePinho
Journal: Cancer Research (2023)

Abstract Sulfation of proteins, carbohydrates, lipids, and xenobiotics is an essential post-translational modification (PTM) process thought to play critical roles in diverse biological processes ranging from detoxification, cell signaling, and extracellular matrix architecture, to immune modulation. Sulfation is accomplished by the universal sulfate donor, PAPS (3'-Phosphoadenosine-5'-phosphosulfate), which is synthesized by bifunctional enzymes PAPSS1 and PAPSS2 (PAPS synthases). The PAPSS2 gene situates near PTEN and is frequently deleted with PTEN across cancer types. Approximately 20% of prostate cancer patients exhibit loss of PTEN, and ~50% of these cases also sustain a loss of PAPSS2. However, the loss of PAPSS2 appears to be tolerated and possibly compensated by its functionally redundant paralogue, PAPSS1, located on chromosome 4q24. The functional redundancy between PAPSS1 and PAPSS2 suggests that these two genes may be collateral lethality pair provided that sulfation is essential for cancer cell viability. Thus, we hypothesize that targeting PAPSS1 in PTEN/PAPSS2-null prostate cancer can generate cancer-specific vulnerabilities while leaving normal cells undisturbed. To assess this possibility, knockdown and knockout of PAPSS1 in cell lines of PAPSS2-null and PAPSS2-wildtype background were generated to characterize cell viability in vitro and tumor formation in vivo. PAPS and APS, an intermediary product of the sulfation pathway, are measured to verify that no alternative pathways for sulfate donors exist and that the co-extinction of PAPSS1/2 eliminates all avenues of generating sulfate donors. Combined extinction of PAPSS1/2 across multiple cancer cell lines was shown to be tolerated in vitro, and recurrent changes in morphology were observed. Loss of sulfation verified by the disappearance of sulfotyrosine and mass spectrometry measurements of PAPS and APS are pending. Our In vitro results surprisingly indicate that a major PTM, like sulfation is entirely dispensable for cancer cell viability under normal culture conditions. However, PAPSS1/2-null cell lines demonstrated a profound delay in tumor formation and prolonged survival, suggesting that sulfation may be required for stromal and innate immune modulation. Citation Format: Ko-Chien Chen, Yonhong Liu, Chenchu Lin, Er-Yen (Nick) Yen, Francesca Citron, Xingdi Ma, Tan Lin, Philip Lorenzi, Florian Muller, Ronald DePinho. Sulfation is required for prostate cancer xenograft tumor formation but is dispensable for cell viabilityin vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6053.
Abstract 4909: Molecular analysis of small cell lung cancer provides insights into mechanism of action underlying the novel drug combination of lurbinectedin and TIC10/ONC201
Authors: Ashley Sanchez Sevilla Uruchurtu, Nicholas Liguori, Leiqing Zhang, Kelsey Huntington, Lanlan Zhou, Young Lee, Abbas E. Abbas, Christopher G. Azzoli, Wafik S. El-Deiry
Journal: Cancer Research (2023)

Abstract We previously explored the combination of novel imipridone TIC10/ONC201 and small molecule RNA polymerase inhibitor lurbinectedin as a potentially effective treatment regimen for small cell lung cancer (SCLC). Data from cell viability experiments demonstrated synergistic killing of SCLC cells with minimal death of healthy control cells. Analysis of intracellular proteins via Western blot indicated that combinatorial treatment induces the integrated stress response, DNA damage/cell cycle checkpoint responses, and increased apoptosis of tumor cells. We have utilized the Luminex 200 platform to perform analyses of cytokine levels in SCLC cell lines with various genetic alterations before and after ONC201 and lurbinectedin treatment. Our results revealed significant changes in cytokine levels following treatment indicating potential immunomodulatory and angioregulatory effects of ONC201 and lurbinectedin. CCL3, known to recruit and activate granulocytes, was found to be elevated by treatment with lurbinectedin, ONC201 and combination versus control. Angiopoietin 1, which contributes to blood vessel maturation, and angiopoietin 2, which promotes neovascularisation, were elevated by all drug treatments in H1882 SCLC cells. Our ongoing studies are further analysing the importance of specific cytokines in tumor vascularity and in recruitment and killing of SCLC cells by immune cells. Results from these experiments are helping to elucidate the molecular mechanisms underlying SCLC, its immune landscape, and treatment response. Citation Format: Ashley Sanchez Sevilla Uruchurtu, Nicholas Liguori, Leiqing Zhang, Kelsey Huntington, Lanlan Zhou, Young Lee, Abbas E. Abbas, Christopher G. Azzoli, Wafik S. El-Deiry. Molecular analysis of small cell lung cancer provides insights into mechanism of action underlying the novel drug combination of lurbinectedin and TIC10/ONC201. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4909.
Abstract 6097: Determination of <i>BRCA2</i> deletion status by copy number estimation using next generation sequencing to predict prognosis of clinically localized prostate cancer
Authors: Makoto Sumitomo, Takuhisa Nukaya, Eiji Sugihara, Mayu Takeda, Sachio Nohara, Shigeki Tanishima, Masashi Takenaka, Kenji Zennami, Kiyoshi Takahara, Ryoichi Shiroki, Hideyuki Saya
Journal: Cancer Research (2023)

Abstract The significance of BRCA alterations has been implicated in the development of metastatic castration-resistant prostate cancer (PC). On the other hand, the details of the frequency and significance of BRCA alterations in localized PC remain unknown. In this study, we investigated the frequency and clinical significance of BRCA alterations in localized PCs using an in-house next-generation sequencer (NGS) system. NGS analyses revealed that the BRCA2 CN decreased in 17 patients (13.5%) and the BRCA1 CN in six (4.8%). NGS-based CN values were shown to be highly correlated with droplet digital PCR-based CN values. Tissue-specific BRCA expression investigated using the Human Protein Atlas showed that the decreased CN of BRCA2, but not BRCA1, is responsible for the decreased BRCA activity in PC. Ten of the 22 patients with decreased BRCA2 CN were presumed to have somatic heterozygous deletion. There were no observed associations between the heterozygous deletion of BRCA2 and various clinicopathological parameters. Furthermore, three of 10 patients developed biochemical recurrence within 3 months after surgery. Multivariate analyses revealed that the initial prostate-specific antigen levels and BRCA2 CN were independent factors for biochemical recurrence. Our results suggest that a decrease in BRCA2 CN may be used as a biomarker for predicting recurrence after surgery in localized PC. Early screening for somatic alterations in BRCA2 using NGS may help to broadly predict the risk of PC progression. Citation Format: Makoto Sumitomo, Takuhisa Nukaya, Eiji Sugihara, Mayu Takeda, Sachio Nohara, Shigeki Tanishima, Masashi Takenaka, Kenji Zennami, Kiyoshi Takahara, Ryoichi Shiroki, Hideyuki Saya. Determination of BRCA2 deletion status by copy number estimation using next generation sequencing to predict prognosis of clinically localized prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6097.